Heterozygous carriers of the gene for the autosomal recessive syndrome ataxia-telangiectasia (A-T), who are about one percent of the United States population, are predisposed to cancer, especially cancer of the female breast. A-T heterozygotes appear to have an excess risk of certain other cancers, diabetes mellitus, and mortality in midadult life. The A-T gene has been localized to chromosome 11g and tightly linked polymorphic probes can now identify heterozygous carriers in A-T families. A prospective comparison of A-T carriers and non-carriers in the same families is-proposed to estimate precisely the A-T heterozygotes' excess risk of cancer at all sites, female breast cancer, diabetes mellitus, and excess early adult mortality. Blood or tissue pathology specimens will be collected for DNA analysis, and clinical information compiled semi-annually, for A-T blood relatives in 187 already identified and approximately 80 new A-T families. The incidence rates for selected health effects will be compared between carriers and noncarriers after the status of each relative is determined with molecular methods. The association of this gene with other selected cancer sites will be tested independently by the newly developed index-test method. To understand why cancers develop in some, but not all, A-T heterozygotes, a questionnaire-based case control analysis will compare the prevalence of other risk factors in identified gene carriers with and those without breast cancer specifically, or with and without all the other A-T associated cancers. Differences observed in their past exposures to cancer risk factors will provide information about the gene-environmental interactions that produce cancer in A-T heterozygotes, thus leading eventually to measures to prevent cancer in this substantial proportion of the population.